Double hit viral parasitism, polymicrobial CNS residency and perturbed proteostasis in Alzheimer’s disease: A data driven, in silico analysis of gene expression data
Introduction
Alzheimer's disease (AD) is the most common form of dementia. Its incidence increases with age, correspondingly increasing the burden of disease in the growing geriatric population (Robinson et al., 2017). AD is currently an incurable disease. Several hypotheses on its etiology have been put forward to date, exploring the niches of perturbed genetics, epigenetics, proteostasis, as well host – environment interactions, such as infection (Kocahan and Dogan, 2017; Kikis, 2017; Roubaud Baudron et al., 2015). Several studies have attempted to further the understanding of AD etiology by assessing differential gene expression between AD patients and controls in a variety of tissues (Hu et al., 2015; Chappell et al., 2018). Pathway enrichment analyses provide a deeper layer of interpretation on gene expression data, allowing them to be studied as members of interactomes, i.e. functional networks of genes with distinct biological roles. While several studies have focused on either a specific tissue type (Chappell et al., 2018) or scoping / integrative meta-analysis of available CNS data (Puthiyedth et al., 2016), no study to date has attempted to create a structured in silico model of data in the form of a model examining the potential interaction of different tissues in a unified manner.
The aim of this study was to create a data driven, in silico model of AD pathogenesis, employing publicly available gene expression data from the GEO Datasets repository; furthermore, we aimed to examine whether an outside – in model, i.e. peripheral immune vs. CNS model could be substantiated through this approach.
Section snippets
Materials and methods
Fig. 1 provides a workflow of our study, summarizing key points. Below we expand on each step of the analyses and the omics tools used.
The GEO Datasets database (Barrett et al., 2013) was inquired using the keywords “Alzheimer's”, “Dementia”. For the retrieved studies, inclusion criteria were (a) case – control design (b) AD as the “disease” group (c) Homo Sapiens as the tissue source (d) NIH curation. Animal and cell line studies were excluded from the studies, as well as studies that used
Step 1: differential gene expression analyses
Statistically significant DEGs derived from (a) the meta-analysis of the HC studies (187 DEGs) and (b) the individual analyses of the NFT-EC (1538 DEGs) and the PBMC study (480) are presented on Supplementary material 1b. Supplementary Fig. 1 presents overlapping genes between studies via a Venn diagram. Notably, among DEGs in the NFT – EC study, there were several HLA mRNAs (HLA-DQB1, HLA-G, HLA-DOA, HLA-DRB1*0402, HLA-E, HLA-DPB1).
Step 2: functional enrichment and protein – Protein Interaction (PPI) networks
Gene lists determined in Step 1 were supplied to STRING on
Discussion
In this study, we used publicly available gene expression data to construct a data-driven model of AD pathogenesis. Meta-analysis of specimen – grouped data revealed multiple pathways involved in impaired proteostasis, immune system and pathogen – host response alterations in specimens derived from AD patients vs. healthy controls. Among current hypotheses in the literature, the model that would fit these initial observations would be the “immune dysregulation – infectious model”, representing
Author Contributorship Statement
GDV conceived the study, performed the analyses, interpreted the results, wrote the first draft and pre-final draft of this study. GS performed quality control and oversaw the analyses. SGV, CN and HSP provided quality control for the workflow and analyses. TD and KIG provided guidance on the study structure. All authors read and approved of the final draft.
Declaration of Competing Interest
The authors reported no declarations of interest.
References (67)
- et al.
Influenza a virus induces autophagosomal targeting of ribosomal proteins
Mol. Cell Proteom.
(2018) - et al.
Functional amyloid-from bacteria to humans
Trends Biochem. Sci.
(2007) - et al.
Influenza infections and risk of Alzheimer’s disease
Brain Behav. Immun.
(2016) - et al.
Rabies virus phosphoprotein interacts with ribosomal protein L9 and affects rabies virus replication
Virology
(2016) - et al.
The antimicrobial protection hypothesis of Alzheimer’s disease
Alzheimers Dement.
(2018) - et al.
Prediction of MHC class I binding peptides using profile motifs
Hum. Immunol.
(2002) - et al.
Novel insights into NDP52 autophagy receptor functioning
Trends Cell Biol.
(2018) - et al.
Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Abeta amyloid deposits in vivo
Open Biol.
(2016) - et al.
Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors
J. Leukoc. Biol.
(2014) - et al.
NCBI GEO: archive for functional genomics data sets-update
Nucleic Acids Res.
(2013)
A systematic view on influenza induced host shutoff
Elife
The EHEC-host interactome reveals novel targets for the translocated intimin receptor
Sci. Rep.
The nature and extent of contributions by defective ribosome products to the HLA peptidome
Proc Natl Acad Sci U S A
Soluble toll-like receptor 4 impairs the interaction of shiga toxin 2a with human serum amyloid P component
Toxins (Basel)
Soluble toll-like receptor 4 impairs the interaction of shiga toxin 2a with human serum amyloid P component
Toxins (Basel)
Hijacking the translation apparatus by RNA viruses
J. Cell Biol.
Role of blood-brain barrier in Alzheimer’s Disease
J. Alzheimers Dis.
Effects of influenza on alveolar macrophage viability are dependent on mouse genetic strain
J. Immunol.
BLAST+: architecture and applications
BMC Bioinf.
Observations of extensive gene expression differences in the cerebellum and potential relevance to Alzheimer’s disease
BMC Res. Notes
Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged fischer 344 rats and Caenorhabditis elegans
Sci. Rep.
The hypothesis that Helicobacter pylori predisposes to Alzheimer’s disease is biologically plausible
Sci. Rep.
Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model
Sci. Rep.
Intracranial V. Cholerae sialidase protects against excitotoxic neurodegeneration
PLoS One
Human ribosomal protein L18a interacts with hepatitis C virus internal ribosome entry site
Arch. Virol.
Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection
Neuron
Large ribosomal protein 4 increases efficiency of viral recoding sequences
J. Virol.
Macrophages in tuberculosis: friend or foe
Semin. Immunopathol.
Lethal influenza infection: is a macrophage to blame?
Expert Rev. Anti. Ther.
molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s Disease
Front. Aging Neurosci.
More powerful procedures for multiple significance testing
Stat. Med.
Integrated analysis of differential gene expression profiles in hippocampi to identify candidate genes involved in Alzheimer’s disease
Mol. Med. Rep.
Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts
FASEB J.
Cited by (8)
Sleep disorders and Alzheimer's disease pathophysiology: The role of the Glymphatic System. A scoping review
2024, Mechanisms of Ageing and DevelopmentTrained immunity in viral infections, Alzheimer's disease and multiple sclerosis: A convergence in type I interferon signalling and IFNβ-1a
2022, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Polymorphisms in OAS1, as previously mentioned, have been associated with multiple sclerosis risk and the response to IFNβ-1a [17,26]. Epigenetic alterations in OAS1 expression had been previously detected within the framework of IFN-I responses in entorhinal cortex neurons, peripheral blood mononuclear cells in Alzheimer's disease [9] and in IFNβ-1a [27]. In setting of innate immunity, OAS1 networks (containing other IFITMs and OASs) have been detected nasal epithelia infected by SARS-CoV-2 [28,29].
FYN, SARS-CoV-2, and IFITM3 in the neurobiology of Alzheimer's disease
2021, Brain DisordersOutside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer's disease
2021, Brain, Behavior, and Immunity - HealthCitation Excerpt :In our original data, IFITM3 which was part of several significantly enriched gene ontologies (GOs) in the PBMC dataset, the entorhinal cortex dataset and a hippocampal cortex dataset (Benjamini – Hochberg adjusted p-value <0.05; Table 1). These pathways were associated with interferon signaling and viral gene expression (Table 1); Several genes comprising these pathways overlapped between different tissues donated by AD patients (PBMC, HC, EC; See Venn Diagram (Khan and Mathelier, 2017), Fig. 1), as per the tissue interaction concept introduced by our study (Vavougios et al., 2020). In order to determine whether IFITM3 dysregulation could arise secondary to viral infection, we used an AD NFT-EC gene signature to determine whether it overlaps with upregulated genes from viral perturbation experiments in Gene Expression Omnibus (GEO), available via the Enrichr web service (under the GEO Virus Perturbations UP module) (Kuleshov et al., 2016).
- 1
Present address: 70 Deinokratous Street, Athens, Greece.